Fetal cells enter the maternal circulatory system during pregnancy and can persist in low numbers in the blood and tissues for years, even decades. This phenomenon is referred to as fetal microchimerism. Most fetal cells that enter the maternal circulation during pregnancy are of hematopoietic origin, such as nucleated red blood cells, lymphocytes, or hematopoietic stem cells. Remarkably, it has been shown that microchimeric fetal cells can express epithelial, leukocyte, or hepatocyte markers in maternal tissue specimens from women afflicted by a variety of diseases long after pregnancy. This observation suggests that fetal cells may respond to maternal injury by differentiating into multiple cell types, a defining characteristic of stem cells. In recent work, we and others have developed a mouse model to study fetal microchimerism and have discovered that the frequency of fetal cells in the lungs is significantly higher than in other tissues. In a remarkable discovery, we have observed large numbers of fetal cells associated with a lung tumor that developed in a mouse following pregnancy. Our observations on fetal microchimerism in the lung have led us to hypothesize that fetal stem cells harbored in the lungs of women following pregnancy influence the development of lung cancer in women, either by increasing susceptibility of women for lung cancer, or just the opposite, by suppressing the growth and development of lung tumors. To test this hypothesis, we will tag murine fetal cells with two transgenes, one that genetically initiates lung tumors and another that encodes luciferase. We will optically image female mice bearing these cells to screen for bioluminescing lung tumors. We will also use mouse models to explore the relationship between the number of pregnancies and the incidence of lung cancer. In another study, we will screen DNA extracted from lung tumors from women who have given birth to a baby boy or boys for the presence of the Y chromosome. Knowledge gained from this study may lead to the development of new therapies for lung cancer based on the role that fetal cells may play in lung tumorigenesis. In particular, if fetal cells contribute to tumor development, one can envision treating women lung cancer patients with adjuvant therapeutics that effectively target fetally-derived cells, thus sparing healthy tissues. If on the other hand, we discover that fetal cells function to suppress lung tumor growth, the finding could be the basis for development of a new cell therapy. Public Health Relevance: The purpose of this study is to test the hypothesis that fetal stem cells that remain in the lungs of women long after they have been pregnant can influence the development of lung cancer in women, either by increasing susceptibility of women for lung cancer, or just the opposite, by suppressing the growth and development of lung tumors. In considering possible clinical applications stemming from this study, if we find that fetal cells contribute to the development of lung tumors, this knowledge would open the door for the development of new genetically-based therapies for lung cancer that would target the death of fetally-derived tumor cells and leave healthy maternal lung tissue unharmed. If, on the other hand, we find evidence that fetal cells function to keep lung tumor growth in check in women, our findings may lead to a novel cell therapy for the treatment of lung cancer.